Expanding the mutation and clinical spectrum of Roberts syndrome

Abstract

Roberts syndrome and SC phocomelia syndrome are rare autosomal recessive genetic disorders representing the extremes of the spectrum of severity of the same condition, caused by mutations in ESCO2 gene. We report three new patients with Roberts syndrome from three unrelated consanguineous Egyptian families. All patients presented with growth retardation, mesomelic shortening of the limbs more in the upper than in the lower limbs and microcephaly. Patients were subjected to clinical, cytogenetic and radiologic examinations. Cytogenetic analysis showed the characteristic premature separation of centromeres and puffing of heterochromatic regions. Further, sequencing of the ESCO2 gene identified a novel mutation c.244_245dupCT (p.T83Pfs*20) in one family besides two previously reported mutations c.760_761insA (p.T254Nfs*27) and c.764_765delTT (p.F255Cfs*25). All mutations were in homozygous state, in exon 3. The severity of the mesomelic shortening of the limbs and craniofacial anomalies showed variability among patients. Interestingly, patient 1 had abnormal skin hypopigmentation. Serial fetal ultrasound examinations and measurements of long bones diagnosed two affected fetuses in two of the studied families. A literature review and case comparison was performed. In conclusion, we report a novel ESCO2 mutation and expand the clinical spectrum of Roberts syndrome.

Thalidomide promotes degradation of SALL4, a transcription factor implicated in Duane Radial Ray syndrome

“…Mice carrying a heterozygous Sall4 genetrap allele show defects in heart and limb development, partially reminiscent of patients with DRRS or HOS ( Koshiba-Takeuchi et al, 2006 ). Another genetic disorder with a related phenotype is Roberts syndrome, caused by mutations in the ESCO2 gene ( Afifi et al, 2016 ). While ESCO2 similarly encodes for a zinc finger protein and is transcriptionally regulated by ZNF143 ( Nishihara et al, 2010 ), ESCO2 (as well as ZNF143, SALL1, SALL2, and SALL3) protein levels were found to be unchanged in all of our mass spectrometry experiments despite robust and ubiquitous expression ( Figure 1D , Figure 1—figure supplements 1 and 2 and Figure 1—source data 1 – 14 ).…”

Phenotypic Overlap of Roberts and Baller-Gerold Syndromes in Two Patients With Craniosynostosis, Limb Reductions, and ESCO2 Mutations

“…Craniosynostosis is a distinctive sign of BGS as it has been reported in 82% (9/11) of BGS patients with RECQL4 alterations (4, 10–12, 32, 33) but in RBS with ESCO2 pathogenic variants only in the 2 patients herein described and in 2 patients of the literature, for whom no details or images are provided (29). Conversely, hemangioma on the face, recorded in 30 ESCO2 + patients (29, 34, 35) and in only one RECQL4 + patient (10, 32), as well as intellectual disability, assessed in 23 ESCO2 + patients (29, 34) and in 1 RECQL4 + patient (4), are prominent in RBS. In addition, cognitive impairment is more severe in RBS than BGS: most RBS patients show not only developmental delay but also a severe intellectual disability even if marked variability exists between RBS and SC Phocomelia (2).…”

“…Moreover, 90% (10/11) BGS (10–12, 32, 33, 36) and all RBS (14, 27–29, 34, 35, 37, 38) patients present with radial alterations (hypo/aplasia) and most of them manifest additional upper and lower limb malformations. Pre-axial upper limb defects are similar in BGS and RBS: ulnae hypoplasia, club hands, thumbs aplasia/hypoplasia, clinodactyly, and oligodactyly, though humeral reduction can be also present in RBS.…”

“…Several additional anomalies have been observed in BGS and RBS patients with a severe phenotype, who can present multiple additional abnormalities coupling only with one syndrome. Poikiloderma (4, 10, 11, 33), imperforate and/or anteriorly positioned anus (4, 10, 32), feeding difficulties (10, 11, 33), hypospadias and undescended testes (33), and osseous demineralization (11, 33) have been recorded only in BGS patients, while heart defects (14, 27, 29, 34, 35, 38) and enlargement of phallus/clitoris (29) have been reported only in RBS. Before the availability of the molecular test, heart defects as well as seizure, have been included in the spectrum of BGS signs (39) but none of BGS patients with RECQL4 alterations manifested these clinical findings, a data raising the possibility that many patients described in the past had received the wrong diagnosis of BGS, as it has been confirmed in a few cases (7–9).…”

Detection of a Novel Mutation on the Gene ESCO2 in a Pediatric Patient with Syndactyly

“…Gen ESCO2 mã hóa cho protein N-acetyltransferase ESCO 2, vốn đóng vai trò rất quan trọng trong việc phân tách 2 nhiễm sắc thể chị em ở pha S trong chu kỳ phân bào cúa tế bào. Một vài nghiên cứu gần gây đã chỉ ra rằng đột biến trên gen ESCO2 có thể dẫn đến những dị thường ở phôi người trong giai đoạn mang thai, khiến trẻ em sinh ra mang đột biến này mắc phải hội chứng Roberts [10,11]. Đây là một hội chứng bệnh với các đặc điểm như dị dạng xương bàn tay, bàn chân, mặt và hộp sọ, bệnh nhân mắc hội chứng Robert thường mắc phải trạng thái suy giảm trí tuệ với mức độ nặng nhẹ khác nhau.…”